Project Abstract Self-assembled multifunctional aptamer-complex biomaterial for precision medicine Oligonucleotide aptamers are a class of biomaterials that function as molecular ligands with high affinity and specificity for a wide range of biological targets. Similarly to protein antibodies, aptamers bind to their cognate targets via conformational recognition and thus, are often referred to as ?chemical antibodies?. As small-sized oligonucleotide biomaterials, aptamers can be rapidly synthesized and easily conjugated to various functional agents for different clinical needs, and exhibit faster cancer-cell binding ability and deeper tumor-tissue penetration than antibodies. The aforementioned features provide aptamers with notable advantages over protein antibodies for clinical applications, and render them unique biomaterials for clinical use. Anaplastic large cell lymphoma (ALCL) is the most common T-cell lymphoma in children. Biologically, lymphoma cells express high-levels of the surface CD30 receptor, a signaling molecule regulating cell fate and a distinct biomarker for ALCL diagnosis. Genetically, lymphoma cells express the Anaplastic Lymphoma Kinase (ALK) oncogene. Currently, CHOP chemotherapy is the mainstay of treatment for ALK+ ALCL although is not ALCL cell-selective or ALK gene-specific, and has serious adverse side effects. To address these clinical challenges, we will develop a multifunctional aptamer-complex biomaterial through self-assembly of functional oligonucleotides (aptamer and siRNA sequences) and self-loading of therapeutic drugs. The formed aptamer-complex will act via three therapeutic modalities for simultaneous ALK+ ALCL cell- targeted chemotherapy, gene therapy, and immunotherapy. We hypothesize that under CD30 aptamer guidance, the aptamer-complex will specifically target ALCL cells and treat lymphoma through combination of different cellular mechanisms, acting as (i) a chemotherapeutic killing lymphoma cells via cell-targeted drug delivery, (ii) a gene therapeutic silencing ALK oncogene via aptamer-facilitated intracellular delivery of siRNA, and (iii) an immunotherapeutic triggering apoptotic cell death via aptamer-mediated activation of cell CD30 signaling. To validate our hypothesis, the following studies will be conducted: To validate our hypothesis, the following studies will be conducted: Aim 1: Formulation of self-assembled aptamer-complex biomaterial. Aim 2: Functional validation of aptamer-complex. Aim 3: Preclinical study of aptamer-complex for precision therapy of lymphoma. Aim 4: Preclinical pharmacokinetic and toxicity studies of aptamer-complex. Technically, this study capitalizes on aptamer technology to develop a unique multifunctional biomaterial for precision medicine. Scientifically, this study will provide a novel immunotherapeutic approach to treat ALCL by stimulating cellular nave apoptotic signaling via aptamer-mediated activation of CD30 receptors. Clinically, the aptamer-complex will enhance therapeutic efficacy, reduce development of drug resistance in lymphoma cells, and avoid off-target toxicity to normal cells/tissues, by combining three different targeted therapeutic mechanisms.